Improved strategies to control the epidemic of human immunodeficiency virus (HIV) type l are urgently needed. Research suggests that other sexually transmitted diseases (STDs) facilitate HIV transmission and may contribute substantially to the spread of AIDS. It is difficult, however, to establish the causal nature of the STD/HIV interaction in clinic based studies, due to potential confounding. In order to avoid this problem and to assess the impact of reduced STD levels on HIV incidence, we propose to conduct a prospective community based trial of intensive STD treatment and control. Twenty five randomly selected villages in Rakai District, Uganda, will receive the STD intervention, including a modified mass treatment strategy, serological surveillance, active case finding and intensive health education/condom distribution. An equal number of randomly chosen villages will serve as control communities, with equivalent data collection and preventive activities; however, instead of mass treatment, control subjects will be referred for STD treatment if warranted by symptomatology or serological results. The proposed study will build upon a large cohort study in the district. Cohort data indicate that the populations of the villages to be included have very high rates of HIV prevalence (range 10% - 58% for all adults), substantial HIV seroincidence (2.6% per 100 person years for adults aged 15-59), over 10% positive syphilis RPR, and over 10% of adults reporting genital ulcer or discharge on an annual basis. Cumulative follow-up rates have exceeded 80% over the 3 years of the current cohort study. We estimate that HIV and STD rates in this population are sufficiently high to detect a 35% reduction in HIV incidence in response to STD control, with 80% statistical power. Rakai District represents a unique setting for the proposed research, as no other study we know of is based in a similarly large number of villages with such high documented rates of both HIV and STDs. In the proposed modified mass STD treatment, we will use safe and effective drugs, administered as single dose oral regimens to both symptomatic and asymptomatic persons, and additional selected therapeutics provided on the basis of symptomatology, physical or laboratory diagnosis. This approach represents the optimum feasible strategy to ensure compliance, good population coverage and therapeutic efficacy in an underserviced area such as Rakai. The study will permit the testing of the mass treatment approach, a strategy of great potential value in other underserviced settings in the world. Due to the research nature of this project, the mass treatment will be backed up by intensive follow-up, surveillance and evaluation.